Pemphigus vulgaris (PV) is a chronic autoimmune disease targeting skin and mucous membranes, characterized by intraepithelial aphlegmasic flaccid blisters and erosions. It is caused by pathogenic autoantibodies that induce the separation of keratinocytes (KC) from one another, a process known as acantholysis, and leads to the formation of blisters just above the basal layer (Bystryn, 2005). The natural course of the disease is progressive with death occurring within a few years of onset due to sepsis in untreated patients (Veldman, 2008). The standard therapy (glucocorticosteroids) can have severe side effects, and some patients do not respond. Therefore there is a great need for new therapeutic approaches for this serious skin disease. The goal of this application is to develop a novel approach to PV therapy based on the 17 nicotinic acetylcholine receptor selective agonist, GTS-21. This agonist is predicted to promote stable KC cohesion and reverse acantholysis, based on the known function of the cholinergic system to maintain epidermal homeostasis. GTS-21 is also expected to mediate anti-inflammatory and immunosuppressive effects in part due to its well-documented suppression of cytokine synthesis in various model systems. We will test the hypothesis that GTS-21 will block phosphorylation signaling events that lead to acantholysis in KCs stimulated with autoantibodies derived from PV patient serum (PV IgG). We will also test a new theory that GTS-21 will inhibit PV IgG-induced production of cytokines (TNF-1 and IL-11) from cultured KCs that normally promote the acantholytic process. The ability of GTS-21 to prevent IV IgG-induced loss of KC cohesion will be tested in an in vitro acantholysis assay. A neonatal mouse model of PV will be used to evaluate the efficacy of GTS-21 to prevent IV-IgG-induced skin blistering and acantholysis. The findings of these studies will provide the basis for future commercialization of this drug, ultimately leading to clinical trials in PV patients. GTS-21 has a unique mechanism of action compared to standard therapies for PV and may be especially useful for patients refractory to standard therapies. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a novel therapy for the life-threatening skin disease, pemphigus vulgarus.